rs1052165

Variant names:

• chr12-55957562-G-A
• rs1052165
• NM_001384361.1:c.741C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-55957562-G-A
• chr12-55957562-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001384361.1(PMEL):​c.741C>T​(p.Pro247Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,526 control chromosomes in the GnomAD database, including 64,508 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (4213 hom., cov: 31)
  • Exomes 𝑓: 0.28 (60295 hom.)
• Consequence: PMEL NM_001384361.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 29 publications found

Genes affected

PMEL (HGNC:10880): (premelanosome protein) This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP7: Synonymous conserved (PhyloP=3.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384361.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMEL	NM_001384361.1	MANE Select	c.741C>T	p.Pro247Pro	synonymous	Exon 6 of 11	NP_001371290.1	P40967-1
	PMEL	NM_001200054.1		c.741C>T	p.Pro247Pro	synonymous	Exon 6 of 11	NP_001186983.1	P40967-2
	PMEL	NM_006928.5		c.741C>T	p.Pro247Pro	synonymous	Exon 7 of 12	NP_008859.1	P40967-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMEL	ENST00000548747.6	TSL:1 MANE Select	c.741C>T	p.Pro247Pro	synonymous	Exon 6 of 11	ENSP00000448828.1	P40967-1
	PMEL	ENST00000449260.6	TSL:1	c.741C>T	p.Pro247Pro	synonymous	Exon 6 of 11	ENSP00000402758.2	P40967-2
	PMEL	ENST00000548493.5	TSL:2	c.741C>T	p.Pro247Pro	synonymous	Exon 7 of 12	ENSP00000447374.1	P40967-1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31905 AN: 151668 Hom.: 4217 Cov.: 31

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.259 AC: 65187 AN: 251430 AF XY: 0.274

Gnomad AFR exome AF: 0.0503

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.282 AC: 411719 AN: 1461740 Hom.: 60295 Cov.: 37 AF XY: 0.287 AC XY: 208491 AN XY: 727182

African (AFR) AF: 0.0467 AC: 1565 AN: 33480

American (AMR) AF: 0.165 AC: 7377 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 8068 AN: 26130

East Asian (EAS) AF: 0.262 AC: 10389 AN: 39700

South Asian (SAS) AF: 0.390 AC: 33628 AN: 86254

European-Finnish (FIN) AF: 0.232 AC: 12409 AN: 53416

Middle Eastern (MID) AF: 0.278 AC: 1602 AN: 5768

European-Non Finnish (NFE) AF: 0.288 AC: 319992 AN: 1111880

Other (OTH) AF: 0.276 AC: 16689 AN: 60392

GnomAD4 genome AF: 0.210 AC: 31882 AN: 151786 Hom.: 4213 Cov.: 31 AF XY: 0.209 AC XY: 15515 AN XY: 74138

African (AFR) AF: 0.0559 AC: 2316 AN: 41442

American (AMR) AF: 0.186 AC: 2835 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3470

East Asian (EAS) AF: 0.255 AC: 1314 AN: 5152

South Asian (SAS) AF: 0.388 AC: 1848 AN: 4758

European-Finnish (FIN) AF: 0.230 AC: 2422 AN: 10550

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19304 AN: 67898

Other (OTH) AF: 0.210 AC: 442 AN: 2108

Alfa AF: 0.263 Hom.: 13909

Bravo AF: 0.197

Asia WGS AF: 0.342 AC: 1189 AN: 3478

EpiCase AF: 0.285

EpiControl AF: 0.284

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.3
DANN	Benign	0.84
PhyloP100		3.2
Mutation Taster		=65/35	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1052165; hg19: chr12-56351346; COSMIC: COSV59388590; COSMIC: COSV59388590;